These investigations will be aimed at elucidating hormone physiology at the level of the brain capillary wall, i.e., the blood-brain barrier (BBB). Our studies will examine both hormone transport and hormone action at the BBB. Despite the increasing awareness that many hormones act within the CNS, there is a paucity of quantitative data bearing on how circulating hormones are transported through the BBB into brain. We believe specific, heretofore unidentified, receptor-transport systems exist within the BBB that medite the flux of hormones through this membrane. Moreover, the capacity/affinity ratio of BBB binding and transpot of circulating hormones may be equal to or even greater than the capicity/affinity ratio of plasma protein binding of the hormone. Such a setting would allow the BBB to "strip" protein-bound hormone off the plasma protein and directly transport the hormone into brain. We have recently obtained evidence that such protein-bound ligands as tryptophan, triiodothyronine, and progesterone, are stripped off the plasma proteins by BBB transport systems. Therefore a fraction of the protein-bound hormone, not the free hormone is the major plasma moiety transported into brain. Our second area of investigation will be aimed at hormone action at the BBB. Preliminary evidence indicates the transport of circulating essential nutrients into brain, e.g., glucose, amino acids, ketone bodies, is selectively modulated by such hormones as insulin, growth hormone, adrenal or thyroid hormones. Since these essential metabolites are precursors to many substrate-limited pathways of brain metabolism, hormonal modulations of BBB transport of metabolic substrates may have profound influences on cerebral metabolism and function. All studies will be done in vivo with a tissue sampling-single injection technque. In addition, we have recently developed an in vivo competitive ligand binding assay that quantitates the local capillary concentration of BBB hormone transport systems.